Divergent access to 5,6,7-perifused cycles

Nitrogen-containing heterocycles are the key components in many pharmaceuticals and functional materials. In this study, we report a transition metal-catalyzed high-order reaction sequence for synthesizing a structurally unique N-center 5,6,7-perifused cycle (NCPC). The key characteristics include the formation of a seven-membered ring by the 8π electrocyclization of various alkenes and aromatic heterocycles as π-components, in which metal carbene species are generated that further induce the cleavage of the α-C-H or -C-C bond. Specifically, the latter can react with various nucleophilic reagents containing -O, -S, -N, and -C. The stereo-controlled late-stage modification of some complicated pharmaceuticals indicates the versatility of this protocol.

Remarks to the Author: The preparation of N-center perifused cycles is a long-term challenge in organic synthesis. Li and coworkers have reported a transition metal-catalyzed high-order reaction sequence for synthesizing a structurally unique N-center 5,6,7-perifused cycle. This is a highly impressive work. This manuscript provides a practical and efficient strategy for the preparation of structurally unique and novel nitrogen-containing heterocycle, including some interesting tetra-and pentacyclic N-center 5,6,7perfused cycle skeletons. Base on my own knowledge in this fields, this is a breakthrough progress. The reactions generally proceed with high-order cascade sequence, avoiding the cumbersome multistep process and presenting a diverse range of substrates and good functional group tolerance. Benzene as π-component are not good functional groups in typical electrocyclization reactions. In most of the reported electrocyclization reactions, the electron-rich aromatics are far more reactive than those benzene as well as their analogues. However, I suggest the authors do additional trials to investigate the possibilities for the involvement of benzene. Typically, the metal carbene intermediate may also trigger intramolecular 1,2-alkyl migration. In this reaction the ring enlargement products by the releasing of the strain of three membered ring were detected? These results will be important and should be discussed in the manuscript. In general, this is a high-quality manuscript that provides a high-order reaction sequence for efficient and divergent access to N-center 5,6,7-perifused cycle skeletons. The gram-scale level and the latestage modifications of pharmaceuticals are well performed. And the mechanism is relatively clear from some control experiments. The supporting information is also thorough and provides all the expected data. Considering the novelty and the importance of this work, I recommend it publishing in nature communications after minor revisions. Some additional questions: 1. Some mistakes should be corrected in text and SI. For example, the "wittig regent" should be corrected into "wittig reagent" in SI. 2. Could the metal carbene be directly captured by nucleophilic reagents when the propargyl position is a quaternary carbon rather than a three-membered ring? 3. For the deuterated experiment of 1a′, Where has deuterium atom gone? The author should give some explanation.
Reviewer #2: Remarks to the Author: The manuscript descried by Li and coworkers reported an interesting cascade annulation reaction to access a series of N-center perifused multicycles compounds. The key features are the formation of medium by an unusual 8π electrocyclization reaction to achieve final fused tricycle system, overcoming the issue of medium-size and multi-fused cycle ring-strain. The final tricycle skeletons could be construction by the both a-C-H or -C-C cleavage initiated by metal a complicated carbene intermediate. Therefore, it should be acceptable after minor revisions. 1. What is the diastereoisomer ratio for the substrate 3? Is it a single diastereoisomer? Its relative configuration and dr value should be confirmed. 2. When the NaOAc were used as nucleophilic reagents, the NaOH as a side product should be generated. It may be unamiable for reaction time or the yield. Have you tried acetic acid as nucleophilic reagent. 3. The DDQ oxidized side-chain rather than the single bond of core tricycle skeleton. What reason causes this chemoselectivity? The result should be discussed in the manuscript. 4. Water as proton donor participated in the reaction process. How to control the amount of water? The detail should be described in the manuscript or SI. 5. The heteroaromatic ring as a π-component participated in the final cyclization. Can benzene ring participate in the cyclization process? The corresponding reaction should be investigated and the result should be putted in manuscript. 6. The title of figure 4a need be revised, because it is not a deuterium experiment but a reaction of deuterated substrate.

Point-by-point responses to reviewers' comments
Response to comments of Reviewer # 1 Recommendation: publish after minor revisions.

Response:
We greatly appreciate your insightful comments and suggestions.
Comment 1: Benzene as π-component are not good functional groups in typical electrocyclization reactions. In most of the reported electrocyclization reactions, the electron-rich aromatics are far more reactive than those benzenes as well as their analogues. However, I suggest the authors do additional trials to investigate the possibilities for the involvement of benzene.
Response: Based on your suggestions, we performed the transformation by using benzene as the π-component, as evidenced by the NMR spectra provided below. Supplementary experiments revealed that the reaction of the phenyl group as the π-component was interrupted during the 5-endo-cyclization step, and subsequent 8π electrocyclization of benzene did not proceed as predicted. We have added this information in our revised manuscript on Page 2: "It may be attributed to the weak aromatic system of the electron-rich furan or thiophene due to uneven charge distribution. The inherent strong aromatic property of benzene makes it difficult to dearomatize in 8π electrocyclization process, resulting that the cascade sequence was interrupted in the 5-endocyclization step." Additionally, the corresponding data has been added to our revised Supplementary Information (on pages S17, S28, S73, S118). 1 H NMR spectrum 13 C NMR spectrum 1ad 2ad Comment 2: Typically, the metal carbene intermediate may also trigger intramolecular 1,2-alkyl migration. In this reaction the ring enlargement products by the releasing of the strain of three membered ring were detected? These results will be important and should be discussed in the manuscript.

Response:
We did not detect any 1,2-alkyl migration products in all of our reactions. Instead, the metal carbene triggered the nucleophilic ring-opening process of the three-membered ring, which resulted in the complete release of ring strain. This process is thermodynamically favorable compared to the formation of a fourmembered ring through 1,2-alkyl migration. There are numerous examples illustrating this phenomenon (Selected examples, J. Am. Chem. Soc. 122, 11549-11550 (2000); J. Am. Chem. Soc. 123, 10511-10520 (2001);Chem. Soc. Rev. 33, 431-436 (2004)). We have included a corresponding description in our revised manuscript on Page S3.
Comment 3: Some mistakes should be corrected in text and SI. For example, the "wittig regent" should be corrected into "wittig reagent" in SI.

Response:
We apologize for the oversight. We have corrected the term "wittig regent" to "wittig reagent" in our revised Supplementary Information (pages S3, S5).

Comment 4:
Could the metal carbene be directly captured by nucleophilic reagents when the propargyl position is a quaternary carbon rather than a three-membered ring?

Response:
We thank this referee for the valuable suggestions. We prepared the pyridine substrates with a quaternary carbon at the -position (as indicated by the NMR spectra provided below). Both the substrates bearing phenyl and methyl groups were tested in our reactions. However, we did not observe any products under the standard reaction conditions, with the starting materials recovered in good yields. We have added the corresponding data in our revised Supplementary Information (pages S7, S17, S74, S75). 1 H NMR spectrum 13 C NMR spectrum 1ae 1af Comment 5: For the deuterated experiment of 1a', Where has deuterium atom gone? The author should give some explanation.
Response: Based on our control experiments, it was observed that the metal carbene induced -C-D cleavage of the intermediate II can lead to the formation of a vinyl metal intermediate III, with a subsequent release of the deuterium atom within this step (as depicted in the figure below). A detailed description of this process has been presented in the mechanism discussion in our manuscript as depicted below.